Irradiation-induced normal tissue damage is a major dose-limiting factor in the treatment of non-small cell lung carcinoma (NSCLC). Severe esophagitis of Grade 3 or 4 occurs in approximately 30% of patients during their over 25% of surviving patients by significant irradiation fibrosis occurring 6 months-2 years after RT. These irradiation-induced effects are exacerbated by chemotherapy. Prevention of normal tissue damage may allow for increased doses of chemotherapy and irradiation thus increasing both clinical response and survival in NSCLC. We have demonstrated significant reduction in inflammatory cytokine response, esophagitis, organizing alveolitis (fibrosis), and radiosensitization of orthotopic Lewis lung (3LL) carcinoma tumors with increased survival in a mouse model by manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) complex injections 24 hours prior to irradiation. Project #4 of the UPCI Lung Cancer SPORE proposes to demonstrate in clinical trials that over-expression of MnSOD in normal tissue projects chemoradiotherapy (CRT)-induced damage. In the first specific aim, we will demonstrate in clinical trial biweekly MnSOD-PL administration to the esophagus will result in decreased esophagitis in lung cancer patients undergoing CRT. The optimal biological effective dose, safety of MnSOD-PL, and prevention of esophagitis will be evaluated. In the second specific aim, the effectiveness of a known lung radioprotective protocol of intratracheal (IT) administered MnSOD-PL in radiosensitization of orthotopic 3LL tumors will be optimized in a mouse model. In the third specific aim, a clinical trial will evaluate the use of inhalation of free-dried MnSOD-PL in radiosensitizing primary NSCLC tumors during CRT. Parameters to be studied include optimizing the biological effective dose, safety of intraesophageal (swallowed), and inhalation MnSOD-PL administration, and effectiveness of normal tissue protection during radiosensitization of tumors. Methods include clinical trials management, histopathology, esophagoscope and biopsy, bronchoalveolar lavage (BAL), cytokine level measurements, nested RT- PCR, and biochemistry. These studies should lead to both an improved quality of life and potential for dose escalation in lung cancer patients requiring CRT.